By regulating immune responses, pain, and pruritus, sensory nerves play an essential role in the initiation or aggravation of chronic diseases like atopic dermatitis, inflammatory bowel disease, irritable bowel syndrome, asthma, and rheumatoid arthritis. Certain cytokines, notably Interleukin-31 (IL-31) and its related cytokine Oncostatin M (OSM), directly activate sensory neurons, thereby regulating neurogenic inflammation, pruritus, and/or pain. In addition, keratinocytes, which express classical neuronal receptors and release factors that subsequently modulate the function of sensory nerves (itch, pain) are a forefront of neuronal signaling in the skin. To test this hypothesis, we propose to investigate the impact of IL-31 and OSM as novel neuromediators with respect to inflammation, pain and pruritus. Understanding how immune cells talk to nerves and vice versa will lead to novel insights into how the nervous and the immune systems communicate in disease states and to new treatment strategies for these diseases, thus improving quality of life. Our knowledge how nerves and immune cells or keratinocytes communicate during inflammation and pruritic diseases, however, is still very poor. There is also a need for better therapies for pruritic and painful diseases in which cytokines are involved. Our preliminary results strongly indicate that skin sensory nerves are directly involved in IL-31-and OSM-induced signalling. In addition, IL-31 and OSM are capable of releasing factors from keratinocytes which subsequently regulate neuronal function during inflammation and pruritus/pain. Based on these new findings, we hypothesize that IL-31 and OSM alone and/or in combination, activate subsets of dorsal root ganglion (DRG) and spinal cord (SC) neurons and keratinocytes through their receptors, thereby regulating neurogenic inflammation, pruritus and/or pain. We will test this hypothesis in three specific aims: Aim 1: To test the hypothesis that receptors for IL-31 and OSM are expressed in neurochemically distinct subsets of primary afferents in mice and humans, and that these neurons innervate peripheral (skin) and central (spinal cord) tissues that express these cytokines. Aim 2: To test the hypothesis that IL-31 and OSM regulate inflammation, pruritus and pain via an action on primary afferent neurons as well as keratinocytes. Aim 3: To test the hypothesis that IL-31 and OSM contribute to neurogenic inflammation, pruritus, and pain using behavioral mouse models in vivo. The significance of this study is that it seeks to prove the concept that classical immune cytokine receptors act as important neuronal cytokine receptors on sensory nerves, thereby regulating skin inflammation, pruritus, and/or pain. This may lead to novel therapeutic strategies to combat skin diseases that have a neuronal component, like atopic dermatitis and other eczemas, or rosacea, and to reduce the adverse symptoms associated with these conditions, including pruritus and pain.